1These authors contributed equally to this study.Abbreviations used: AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionate; BDNF, brain-derived neurotrophic factor; CMS, chronic mild stress; NAc, nucleus accumbens; PFC, prefrontal cortex; VTA, ventral tegmental area. AbstractExposure to chronic mild stress (CMS) is known to induce anhedonia in adult animals, and is associated with induction of depression in humans. However, the behavioral effects of CMS in young animals have not yet been characterized, and little is known about the long-term neurochemical effects of CMS in either young or adult animals. Here, we found that CMS induces anhedonia in adult but not in young animals, as measured by a set of behavioral paradigms. Furthermore, while CMS decreased neurogenesis and levels of brainderived neurotrophic factor (BDNF) in the hippocampus of adult animals, it increased these parameters in young animals. We also found that CMS altered a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor GluR1 subunit levels in the hippocampus and the nucleus accumbens of adult, but not young animals. Finally, no significant differences were observed between the effects of CMS on circadian corticosterone levels in the different age groups. The substantially different neurochemical effects chronic stress exerts in young and adult animals may explain the behavioral resilience to such stress young animals possess.

Stress is defined in biological systems as any condition that seriously perturbs physiological/psychological homeostasis and well known to affect the function and morphology of the hippocampus (Kim and Diamond 2002). The exact underlying cellular mechanisms that mediate the inhibitory effect of stress are largely unknown. However, stress reduces the expression of several growth factors and neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1, nerve growth factor, epidermal growth factor, and vascular endothelial growth factor, that can all influence neurogenesis (Lucassen et al. 2010). Address correspondence and reprint requests to Dr Kiyofumi Yamada, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan. E-mail: kyamada@med.nagoya-u.ac.jp 1 These authors contributed equally to this study.Abbreviations used: BDNF, brain-derived neurotrophic factor; BrdU, 5-Bromo-2¢-deoxyuridine; DCX, doublecortin; DG, dentate gyrus; GCL, granule cell layer; GFAP, glial fibrillary acidic protein; NeuN, neuronal nuclei; Npas4, neuronal PAS domain protein 4; PBS, phosphate-buffered saline; SGZ, subgranular zone; Sox-2, SRY-related HMG box 2. AbstractNeurogenesis in the hippocampus occurs throughout life in a wide range of species and could be associated with hippocampus-dependent learning and memory. Stress is well established to seriously perturb physiological/psychological homeostasis and affect hippocampal function. In the present study, to investigate the effect of chronic restraint stress in early life on hippocampal neurogenesis and hippocampus-dependent memory, 3-week-old mice were subjected to restraint stress 6 days a week for 4 weeks. The chronic restraint stress significantly decreased the hippocampal volume by 6.3% and impaired hippocampal neurogenesis as indicated by the reduced number of Ki67-, 5-bromo-2¢-deoxyuridine-and doublecortin-positive cells in the dentate gyrus. The chronic restraint stress severely impaired hippocampus-dependent contextual fear memory without affecting hippocampus-independent fear memory. The expression level of brain-specific transcription factor neuronal PAS domain protein 4 (Npas4) mRNA in the hippocampus was down-regulated by the restraint stress or by acute corticosterone treatment. Npas4 immunoreactivity was detected in progenitors, immature and mature neurons of the dentate gyrus in control and stressed mice. Our findings suggest that the chronic restraint stress decreases hippocampal neurogenesis, leading to an impairment of hippocampus-dependent fear memory in mice. Corticosteroneinduced down-regulation of Npas4 expression may play a role in stress-induced impairment of hippocampal function.

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